Population Pharmacokinetics and Monte Carlo Simulation of Cefepime in Critically Ill Patients with Hospital-Acquired/Ventilator-Associated Pneumonia

Seo Hyeonji; Kim Yong Kyun; Park Sunghoon; Kim Hwan-il; Lee Dong-Hwan

doi:10.3947/ic.2022.0087

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저자정보: Seo Hyeonji (Division of Infectious Diseases Department of Internal Medicine Hallym University Sacred Heart Hospital Hallym University College of Medicine Anyang Korea.) Kim Yong Kyun (Division of Infectious Diseases Department of Internal Medicine Hallym University Sacred Heart Hospital Hallym University College of Medicine Anyang Korea.) Park Sunghoon (Division of Pulmonary Allergy and Critical Care Medicine Department of Internal Medicine Hallym University Sacred Heart Hospital Hallym University College of Medicine Anyang Korea.) Kim Hwan-il (Division of Pulmonary Allergy and Critical Care Medicine Department of Internal Medicine Hallym University Sacred Heart Hospital Hallym University College of Medicine Anyang Korea.) Lee Dong-Hwan (Department of Clinical Pharmacology Hallym University Sacred Heart Hospital Hallym University College of Medicine Anyang Korea.)

저널정보: 대한감염학회 Infection and Chemotherapy Infection and Chemotherapy 제55권 제1호

발행연도: 2023.3

수록면: 29 - 41 (13page)

DOI: 10.3947/ic.2022.0087

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Background This study aimed to investigate the population pharmacokinetics (PK) profile and determine the optimal dosage regimen of cefepime in critically ill adult patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP). Materials and Methods Population-PK models for cefepime were developed using a nonlinear mixed-effect modeling approach. The percentage of time within 24 h in which the free concentration exceeded the minimum inhibitory concentration (MIC) at a steady state (50%fT>MIC, 100%fT>MIC, and 100%fT>4×MIC) for various combinations of dosage regimens and renal function was explored using Monte Carlo simulation. Results Twenty-one patients were prospectively enrolled in this study. Cefepime PK was best described using a two-compartment model in which creatinine clearance (CLCR) through Cockcroft-Gault (CG) was a significant covariate for the total clearance of cefepime. The simulation results to determine the optimal cefepime dosing regimen for 50%fT>MIC as treatment target with Cmin <20 mg/L as safety target showed that a dosage regimen of 2 g through intravenous (IV) infusion every 12 h administered over 4 h was optimal at an MIC of 4 mg/L, rather than the currently recommended dosage regimen of 2 g administered through IV infusion every 8 h, in patients with normal renal function (CLCR = 90 - 130 mL/min). For a treatment target of 100%fT>MIC with Cmin <35 mg/L as a safety target, a dosage regimen of 0.75 g administered through continuous infusion over 24 h would be sufficient at an MIC equal to or less than 8 mg/L in patients with renal dysfunction (CLCR = 10 - 30 mL/min). Conclusion Our results suggest that clinicians should consider renal function and potential neurotoxicity when deciding the dosing regimen of cefepime in critically ill patients with HAP or VAP. Therapeutic drug monitoring (TDM) to adjust cefepime trough levels may be useful to improve clinical outcomes and reduce cefepime neurotoxicity.

Background This study aimed to investigate the population pharmacokinetics (PK) profile and determine the optimal dosage regimen of cefepime in critically ill adult patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP). Materials and Methods Population-PK models for cefepime were developed using a nonlinear mixed-effect modeling approach. The percentage of time within 24 h in which the free concentration exceeded the minimum inhibitory concentration (MIC) at a steady state (50%fT>MIC, 100%fT>MIC, and 100%fT>4×MIC) for various combinations of dosage regimens and renal function was explored using Monte Carlo simulation. Results Twenty-one patients were prospectively enrolled in this study. Cefepime PK was best described using a two-compartment model in which creatinine clearance (CLCR) through Cockcroft-Gault (CG) was a significant covariate for the total clearance of cefepime. The simulation results to determine the optimal cefepime dosing regimen for 50%fT>MIC as treatment target with Cmin <20 mg/L as safety target showed that a dosage regimen of 2 g through intravenous (IV) infusion every 12 h administered over 4 h was optimal at an MIC of 4 mg/L, rather than the currently recommended dosage regimen of 2 g administered through IV infusion every 8 h, in patients with normal renal function (CLCR = 90 - 130 mL/min). For a treatment target of 100%fT>MIC with Cmin <35 mg/L as a safety target, a dosage regimen of 0.75 g administered through continuous infusion over 24 h would be sufficient at an MIC equal to or less than 8 mg/L in patients with renal dysfunction (CLCR = 10 - 30 mL/min). Conclusion Our results suggest that clinicians should consider renal function and potential neurotoxicity when deciding the dosing regimen of cefepime in critically ill patients with HAP or VAP. Therapeutic drug monitoring (TDM) to adjust cefepime trough levels may be useful to improve clinical outcomes and reduce cefepime neurotoxicity.

#Cefepime #Population pharmacokinetics #Hospital-acquired pneumonia #Ventilator-associated pneumonia #Monte Carlo simulation

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Seo Hyeonji

소속기관 Division of Infectious Diseases Department of Internal Medicine Hallym University Sacred Heart Hospital Hallym University College of Medicine Anyang Korea.

주요연구분야 의약학 > 임상의학 > 내과학

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Kim Yong Kyun

소속기관 Division of Infectious Diseases Department of Internal Medicine Hallym University Sacred Heart Hospital Hallym University College of Medicine Anyang Korea.

주요연구분야 의약학 > 임상의학 > 내과학

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Park Sunghoon

소속기관 Division of Pulmonary Allergy and Critical Care Medicine Department of Internal Medicine Hallym University Sacred Heart Hospital Hallym University College of Medicine Anyang Korea.

주요연구분야 의약학 > 임상의학 > 내과학

논문수 1 이용수 0

Kim Hwan-il

소속기관 Division of Pulmonary Allergy and Critical Care Medicine Department of Internal Medicine Hallym University Sacred Heart Hospital Hallym University College of Medicine Anyang Korea.

주요연구분야 의약학 > 임상의학 > 내과학

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Lee Dong-Hwan

소속기관 Department of Clinical Pharmacology Hallym University Sacred Heart Hospital Hallym University College of Medicine Anyang Korea.

주요연구분야 의약학 > 임상의학 > 내과학

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